Project Summary/Abstract Tumor progression ? including resistance to therapy, metastasis, and recurrence ? is responsible for the majority of cancer deaths. Understanding how cancer cells survive treatment, spread to distant sites, persist as dormant residual cells, and eventually recur is essential to improving the treatment of this disease. Our long-term goal is to identify the pathways that regulate these processes in order to prevent or treat tumor recurrence. To achieve this we are using conditional genetically engineered mouse (GEM) models of breast cancer that allow for the mechanistic dissection of the processes of dormancy and recurrence. Using these models, we have identified a functional role for the tumor suppressor par-4 in regulating survival and recurrence of breast cancer cells after therapy. Par-4 is down-regulated in recurrent tumors from three GEM models, and this down-regulation is both necessary and sufficient for tumor recurrence. Similarly, in women with breast cancer, low par-4 expression is associated with a poor response to neoadjuvant therapy and an increased risk of recurrence. However, nothing is known about the upstream pathways that regulate par-4 during dormancy and recurrence. In addition, it is not known what downstream pathways par-4 regulates to inhibit dormant cell survival and recurrence, or how par-4 affects metastasis. This proposal will address these questions. In Aim 1, we will elucidate the pathways that regulate par-4 following oncogene inhibition and in recurrent tumor cells, and determine how these contribute to dormant cell survival and recurrence. In Aim 2, we will identify the molecular pathways regulated by par-4 expression, and determine how these contribute to dormant cell survival and recurrence. In Aim 3, we will dissect the temporal requirements for par-4 down-regulation during dormancy, recurrence, and metastasis. Our work will provide insight into the regulation and function of par-4 during tumor recurrence and may identify opportunities to develop therapies that target dormant cells and prevent tumor recurrence.